Figure 2.

Pluripotency lies on a continuum of successive phases. The figure is based on “Waddington's landscape,” and shows the journey taken by a naive pluripotent cell (ball labeled 1) toward a more differentiated (but still pluripotent) primed state (ball labeled 3). The status of cells transitioning between these two states is not well defined (balls labeled 2). Color of the balls represents the overall transcriptomic state. (Inset, right) Represents “pluripotent phases” as serial populations of cells with differing levels of heterogeneity rather than discrete developmental stages. Importantly, ground-state pluripotency seems to occupy a “lower energy” state in terms of chromatin mobility compared to both two-cell-stage embryos and serum-cultured embryonic stem cells (ESCs) (Bošković et al. 2014), which may also explain the relatively lower transcriptional promiscuity among naive pluripotent populations (Tosolini et al. 2018). Prior to commitment to a particular primed state, cells may be found in a heterogeneous mix of transcriptomic and metabolic states. This has been somewhat recapitulated in vitro with serum-grown ESCs, which have been described to possess a “confused” transcriptome. However, to what extent there exists a phenotypically distinct “formative” phase between naive and primed pluripotency, or whether this state is strictly necessary for lineage commitment, remains poorly understood.